CN1019890C - Process for preparation of 4-heterocyclic sulfonyl (or thio-) propyl-oxy-2-hydroxy-3-propyl-hypnone derivatives - Google Patents

Abstract

The present invention relates to some novel antiallergic drugs and a preparation method thereof.

Description

The present invention relates to some novel compounds with antiallergic activity and their preparation methods.

Certain types of cells, such as mast cells, release several chemical transmitters that convey the allergic response in response to antigen-antibody responses. Histamine and SRS-A (slow reacting substance) are considered important as chemotransmitters participate in the immediate allergic response. But the latter is most important for bronchial asthma. SRS-A is a mixture of leukotriene C ₄ (LTC ₄ ), leukotriene D ₄ (LTD ₄ ) and leukotriene E ₄ (LTE ₄ ), which is passed through the fat (fat) oxygenase pathway The resulting metabolites of eicosatetraenoic acid. In general, drug research for the prevention, alleviation and elimination of allergic symptoms is directed towards the development of drugs that inhibit the release of chemical mediators or antagonize their effects. As a result, antihistamines (e.g., diphenhy dramine and chlorpheniramine, etc.), SRS-A release inhibitors (disodium cromoglycate), etc. were launched. However, the anti-bronchial asthma effect of the former is unreliable, while the latter has only a preventive effect and has no effect when taken internally.

Therefore, some drugs which can antagonize the action of SRS-A can be expected to be used as antiallergic drugs. At this time, only a few drugs are known to have this activity, and none of them are known to have this activity when taken internally.

As a result of extensive research on compounds having an antiallergic effect, the present inventors have found that a novel class of compounds represented by the chemical formula (I) has an excellent antiallergic effect, especially on compounds represented by SRS-A. The induced anaphylaxis has an extremely strong inhibitory effect, even if taken internally.

[wherein Ar represents a pyrazole (Pyrazolo) [1,5-a] pyridin-3-yl ring, which may or may not have a substituent of a linear or branched chain alkyl group of 1 to 4 carbon atoms, or represents benzimidazol-2-group, and n represents an integer between 0 and 2].

According to the present invention, the compounds represented by the general formula (I) can be produced by various routes.

(1). The compound in which n is O in the general formula (I) can be produced by reacting the compound of the general formula (II) with a phenoxyalkyl derivative of the general formula (III). Typically they can be obtained by letting the compound of general formula (II) dissolve in a suitable solvent (for example, methanol, ethanol, tetrahydrofuran, etc.) etc.) in the presence of the phenoxyalkyl derivatives of the general formula (III) to react to produce.

[wherein Ar is the same as described above].

[wherein, X is a halogen atom]

(2). The compound wherein n is 0 represented by the general formula (I) can also be converted into a compound of the general formula (II) by converting the compound of the general formula (IV) into a compound of the general formula (II), and then follow the same method as (1) Method The compound of the general formula (II) is reacted with the compound of the general formula (III) to produce it. Typically, a suitable reagent (for example, zinc-hydrochloric acid, sodium borohydride, potassium hydroxide, etc.) is used in a suitable solvent (for example, methanol, ethanol, etc.) to make the compound of general formula (IV) into compounds of general formula (II).

[wherein Ar represents the same as described above].

(3). The compound represented by the general formula (I) in which n is 1 can be produced by reacting the compound represented by the general formula (I) in which n is 0 with an oxidizing agent. Typically, they can be obtained by making the compound represented by the general formula (I) wherein n is 0 and one or several volume molar equivalents of a mild oxidizing agent (for example, hydrogen peroxide in methanol, dichloromethane m-chloroperbenzoic acid, etc.) in the reaction to manufacture.

(4). The compound represented by the general formula (I) but n is 2 can be prepared by reacting the compound represented by the general formula (I) wherein n is 0 with an oxidizing agent in the same manner as described in (3). manufacture. Typically they can also be prepared by reacting the compound represented by general formula (I) wherein n is 0 in the same manner as described in (3) with two or more molar equivalents of a suitable oxidizing agent To be manufactured.

In the following, the present invention will be illustrated by some specific examples, but the present invention is not limited to these examples.

Reference example 1

Manufacture of 2-isopropyl-3-thiocyanatopyrazolo[1,5-a]-pyridine. To a solution of 3 g of 2-isopropylpyrazolo[1,5-a]pyridine in 56 ml of methanol was added 5.74 g of sodium thiocyanate and stirred at room temperature. Another 3.3 g of bromine was dissolved in 13 ml of methanol saturated with potassium bromide, and then added drop by drop to the above solution. The mixture was then stirred at room temperature for 1 hour, then poured into 130 ml of water, and the resulting precipitate was filtered off and dried. The coarse precipitate was then recrystallized from methanol to obtain 3.53 (87% yield) of the title compound as pale yellow triangular crystals. The melting point is 91-92.5°C.

Reference example 2

Production of 2-methyl-3-mercaptopyrazolo[1,5-a]pyridine. The compound is It was synthesized by the same method as described in Reference Example 1 using 2-methylpyrazol[1.5-a]pyridine instead of 2-isopropylpyrazol[1,5-a]pyridine. It is a pale yellow powder (50% yield). The melting point is 111-113°C.

Example 1

Manufacture of 2-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylthio]benzimidazole.

To a suspension of 1.2 g of 2-mercaptobenzimidazole in 30 ml of ethanol was added with stirring 580 mg of potassium hydroxide, which was then stirred at room temperature for a further 10 minutes. Next, to this solution was added 2.8 g of 3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl bromide in one portion and stirred at room temperature for 4 hours. Then, the solvent was distilled off under reduced pressure and the residue was diluted with dichloromethane, after which it was extracted three times with dichloromethane. The organic layers obtained three times were mixed together, washed with water saturated with sodium chloride, and dried over anhydrous sodium sulfate. Next, the solvent was distilled off under reduced pressure, and the resulting residue was recrystallized with dichloromethane-n-hexane to obtain 2.5 g (81% yield) of the objective compound, which was A colorless powder. The melting point is 149-150°C.

Analysis (%) for _C24H24N2O3S : Calculated ( _found ); C, 65.60 (65.71); H, 6.29 (6.29); _N , 7.29 ( _7.24 ).

Example 2

Manufacture of 3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylthio]-2-isopropylpyrazolo[1,5-a]pyridine.

To a suspension of 1 g of 2-isopropyl-3-mercaptopyrazol[1,5-a]pyridine (described in Reference Example 1) in 25 ml of methanol was added 2.6 ml of concentrated hydrochloric acid, and Stir at room temperature. Then 1.3 g of zinc powder was added little by little to the solution, and stirred at room temperature for 1 hour. Thereafter the solution was diluted with 40 ml of water and extracted twice with dichloromethane, then the two organic layers were combined and incubated over anhydrous sodium sulfate. After drying, the solvent was distilled off under reduced pressure. Next, the resulting residue was treated in the same manner as in Example 1, and then purified by flash column chromatography (dichloromethane: benzene = 2: 1), and finally purified with n-hexane Recrystallization from alkanes gave 750 mg (38% yield) of the title compound as colorless needles. The melting point is 99-95.5°C.

Analysis (%) for _C24H30N2O3S : Calculated ( _found ); C, 67.58 (67.70 ₎ ; H, 7.09 (7.19); N, 6.57 ( _6.43 ).

Example 3

Preparation of 3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylthio]-2-isopropylpyrazolo[1,5-a]pyridine-S-oxide .

800 mg of 3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylthio]-2-isopropylpyrazol[1,5 -a] A solution of pyridine (described in Example 2) (cooled to below 0°C with an ice-salt-water bath) was added with 405 mg of m-chloroperbenzoic acid and stirred at 0°C for 15 minutes. Next, 4 g of calcium hydroxide was added to the reaction mixture, which was stirred at room temperature for 10 minutes, and then the precipitate in the suspension was filtered off with celite. The filtrate was further washed with 5% aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. Finally, the crystallized residue was recrystallized from dichloromethane-n-hexane to obtain 770 mg (93% yield) of the title compound as a colorless powder. The melting point is 145-146°C.

Analysis (%) for _C24H30N2O4S : Calculated ( _found ); C, 65.13 (65.17 ₎ ; _H , 6.83 (6.79); N, 6.33 (6.23).

Example 4

Manufacture of 3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylsulfonic acid]-2-isopropylpyrazol[1.5-a]pyridine.

2 g of 3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylthio]-2-isopropylpyrazol[1,5- a] Pyridine (described in Example 2) Add 2.22 g of m-chloroperbenzoic acid to the solution (cooled in a water bath to below 15°C), and stir at room temperature for 2 hours. The purification procedure remained the same as described in Example 3. The resulting residue was further recrystallized from dichloromethane-n-hexane to obtain 1.93 g (92% yield) of the objective compound as a pale yellow powder. The melting point is 169.5-170.5°C.

Analysis (%) for _C24H30N2O5S : Calculated ( _found ); C, 62.86 (62.70 ₎ ; H, 6.59 (6.66); _N , 6.11 (6.01).

The compounds shown in Table 1 were synthesized using the methods described in Examples 1-4.

The compounds presented here show strong antagonistic effects on LTD4-induced contraction of isolated guinea pig ileum. Notably, all of these compounds are effective orally in experimental models of bronchial asthma. Inhalation of aerosolized antigen into very sensitive guinea pigs pre-treated with indomethacin and picometriol caused allergic bronchoconstriction, in which endogenously released SRS_A played a major role. The compounds of the present invention effectively inhibited this allergic bronchoconstriction at an oral dose of 20 mg/kg (Table 2). A well-known SRS_A antagonist was reported: FPL712: i.e., sodium 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-4 -Oxo-8-propyl-4H-1-benzopyran-2-carboxylate is ineffective when taken orally (P.Shead et al.: Monogr Allergy, PP.244～248.S Karger 1977). Thus, the compounds of the present invention are a class of antiallergic agents having potent anti-SRS-A (leukotriene) activity. These compounds are considered to be of prophylactic and therapeutic value for allergic diseases such as bronchial asthma, allergic rhinitis and urticaria.

Claims (2)

1, a kind of method for preparing the compound of general formula (I) [wherein, Ar represents a pyrazol[1.5-a]pyridin-3-yl ring with or without a substituent of a linear or branched chain alkane having 1 to 4 carbon atoms, or represents a benzimidazole- 2-yl rings, where n is an integer between 0 and 2], which includes: (a) make the compound of general formula (II) [Wherein, the definition of Ar is the same as above] With the phenoxyalkyl derivatives of the compound of general formula (Ⅲ) reacting [wherein, X is a halogen atom]; or/and (b) Oxidation of the compound represented by the general formula (I) wherein n is O. 2. A method for preparing a compound of general formula (I) as claimed in claim 1, wherein the compound of formula (II) is obtained by converting the thiocyanate group in the compound of general formula (IV) into Made from mercapto.